Smoking is a well-known cause of cancer related death, but could also have a dire impact on long-term skeletal health. Risk for fracture and subsequent mortality is already a significant problem among the elderly, and smoking can increase fracture risk almost 1.5 times in women over 65. In the clinic, it is observed that smokers have greater incidences of non-unions and delayed healing after fracture repair, resulting in higher care expenses. While the biological mechanism is somewhat understood, it is still not clear how smoking causes skeletal differences that result in increased fracture risk and impaired fracture healing, leading to the observed clinical outcomes. Studies to-date looking at the macro-scale effects of smoking on bone have mostly focused on imprecise measures of bone structure and strength, with inconsistent results. Characterizing differences due to smoking in bone microstructure, which plays a role in bone strength, and also differences in functional outcomes of bone strength, will further improve our understanding of effects of smoking on the skeletal system. The objectives of this application are to: (Aim 1) characterize in vivo differences in bone microstructure and mechanical strength between smokers and non-smokers (both with and without a previous fracture) using a cross-sectional study design; and, (Aim 2) characterize differences in fracture healing between smokers and non-smokers who present with acute distal radius fractures using a longitudinal-prospective study design. For Aim 1, high-resolution peripheral quantitative computed tomography (HR-pQCT) images of non-dominant forearms will be acquired from all subjects to determine cortical and trabecular microstructure parameters. Also, multiscale micro-finite element (FE) models will be constructed from the HR-pQCT images to evaluate stiffness and fracture strength. These parameters will be compared between smokers and non- smokers and between fracture status using a two-way analysis of variance. For Aim 2, HR-pQCT images of both fractured and contralateral limbs will be acquired within two weeks of fracture (baseline) and following 4 months, at one month intervals. Multiscale micro-FE models of the stages of fracture healing will also be created at all time-points. Microstructure, stiffness and clinical outcomes of fracture healing status will be compared between smokers and non-smokers using mixed linear models. The long-term goal is to develop subject-specific tools to determine quantity or duration of smoking that leads to clinical impairment, and to predict the success or failure of interventions for fracture repair based on current smoking habits. This work will allow for accurate predictions of subject-specific thresholds of smoking that result in increased fracture risk, and objective identification of smoking thresholds that cause poor fracture healing. The effectiveness of preoperative interventions (such as smoking cessation, nicotine replacement therapies etc.) to adequately improve bone quality resulting in successful postoperative outcomes can also be determined, further improving quality of life.